Synaptic plasticity is at least one of the cellular underpinnings of addiction to drugs of abuse. NMDA receptors, which are necessary for some forms of synaptic plasticity, play pivotal roles in mediating behavioral responses to cocaine. Infusion of cocaine can lead to NMDA receptor-dependent long term potentiation of synaptic transmission in the ventral tegmental area (VTA). Infusion of NMDA receptor antagonists into the VTA prevent cocaine-induced conditioned place preference. We will test the novel hypothesis that astrocytes are critical for the control of NMDA receptor function, synaptic plasticity, and as a consequence addictive behaviors. There is a new appreciation for roles of astrocytes in the control of synaptic transmission. In 1994 we discovered that astrocytic Ca2+ signals stimulate the release chemical transmitters from these glia. Since then we and others have shown that this process of gliotransmission can regulate neuronal excitability and synaptic transmission leading to the idea of the Tripartite Synapse, which accounts for roles of astrocytes in synaptic transmission. Using lines of inducible, astrocyte-specific transgenic mice impaired in gliotransmission we have made two observations essential for this project: First, inhibiting gliotransmission significantly reduces synaptic NMDA receptor density. Second, this inhibition of gliotransmission blunts cocaine-induced conditioned place preference. Given the known importance of NMDA receptors in mediating rewarding properties of drugs of abuse we hypothesize that astrocytes regulate neuronal NMDA receptor density and synaptic plasticity and thereby behavioral responses to drugs of abuse. Specific Aim I: Test the hypothesis that gliotransmission regulates functional NMDA receptor density on dopaminergic neurons in the VTA. Specific Aim II: Test the hypothesis that gliotransmission promotes synaptic plasticity in the VTA. Specific Aim III: Test the hypothesis that gliotransmission is essential for cocaine-induced behavioral response. Systematically evaluating the role of gliotransmission in synaptic plasticity and behavioral responses to drugs of abuse promises to offer new insights into the cellular mechanisms underlying addiction. Since astrocytes express unique receptors that could be targeted therapeutically, success in this project may offer a new approach to prevent and treat addictions. PUBLIC HEALTH RELEVANCE: The goal of this work is to evaluate the novel idea that a non-neuronal cell of the brain called the astrocyte plays a pivotal role in mediating the long-term response to drugs of abuse. Systematically evaluating the role of astrocytes in synaptic plasticity and behavioral responses to drugs of abuse promises to offer new insights into the cellular mechanisms underlying addiction and the potential to identify new targets for the development of therapeutics.